Chemical Synthesis of Bioactive Diterpenoids

生物活性二萜类化合物的化学合成

基本信息

批准号：
10405930
负责人：
Christopher D Vanderwal
金额：
$ 42.86万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10405930
关键词：
Address Anti-Bacterial Agents Antibiotics Antimalarials Architecture Area Artemisinins Bicycling Biological Biology Chemicals Chemistry Clinical Cobalt Complex Cyclization Development Diterpenes Equilibrium Goals Hydrazones Investigation Laboratories Lead Life Malignant Neoplasms Methodology Modernization Natural Products Nature Neurologic Organic Chemistry Paclitaxel Polyenes Process Production Research Savings Structure-Activity Relationship Synthesis Chemistry Terpenes Time Work analog bioactive natural products chemical synthesis design empowered innovation novel pre-clinical programs small molecule

Address Anti-Bacterial Agents Antibiotics Antimalarials Architecture Area Artemisinins Bicycling Biological Biology Chemicals Chemistry Clinical Cobalt Complex Cyclization Development Diterpenes Equilibrium Goals Hydrazones Investigation Laboratories Lead Life Malignant Neoplasms Methodology Modernization Natural Products Nature Neurologic Organic Chemistry Paclitaxel Polyenes Process Production Research Savings Structure-Activity Relationship Synthesis Chemistry Terpenes Time Work analog bioactive natural products chemical synthesis design empowered innovation novel pre-clinical programs small molecule

展开

项目摘要

Project Summary Polycyclic terpenoid natural products are endowed with a broad range of medicinally relevant biological activities. Taxol and artemisinin are two premier examples of life-saving terpenoids; the former is used clinically to treat several different cancers, while the latter is a critical antimalarial agent used worldwide. Chemical synthesis approaches to natural products provide opportunities to make compounds that might be scarcely available from nature, to generate analogues that are only available by total synthesis, and to make probe molecules for increased understanding of the underlying biology. A balance of innovative strategy and new chemical methodology promises efficient syntheses that can serve to answer important biological questions that often can only be probed with small molecules. As part of our laboratory’s long-term goal to enhance efficiency in the synthesis of complex natural products to facilitate important studies in biology, the objective of the proposed research program is to develop concise and creative synthesis designs and empowering methodological advances to permit access to many bioactive diterpenoid natural products. The rationale for this work is that synthetic chemistry is critical to the development of natural product “hit molecules” into legitimate preclinical lead compounds by analogue production, by identification of structure-activity relationships, by the synthesis of chemical probe molecules for mechanism of action studies, and more. An efficient total synthesis of targeted natural products provides a platform from which to address each of these key areas of research. The proposed research is significant because chemical synthesis will provide access to a broad range of biologically important secondary metabolites and analogues with which to interrogate key processes; at the same time, the underlying synthesis designs and methodologies will lead to vertical advancement of the field of organic chemistry. These contributions are innovative by virtue of the chemistry-driven, multi-faceted investigations into the biological activity of diterpenoids with immunosuppressive, antiviral, antibiotic, and neurological activity; the development of new stereocontrolled polyene cyclization strategies to access polycyclic diterpenoid natural products; and the elaboration of new radical bicyclization strategies to make complex architectures relevant to bioactive natural products.

项目摘要多循环萜类天然产品具有广泛的药物相关生物学活动。紫杉醇和青蒿素是挽救生命的萜类化合物的两个主要例子。前者在临床上使用治疗几种不同的癌症，而后者是全球使用的关键抗疟药。化学合成天然产品的方法提供了制造可能几乎不可能的化合物的机会从自然中获得，以生成只能通过总合成才能获得的类似物，并证明分子增加对潜在生物学的理解。创新策略和新的平衡化学方法论有望有效的合成，可以回答重要的生物学问题通常只能用小分子探测。作为我们实验室长期目标的一部分，以提高复杂自然综合效率为了促进生物学研究的产品，拟议的研究计划的目的是开发简洁而创意的综合设计，并赋予方法论上的能力，以允许访问许多生物活性数字天然产品。这项工作的理由是合成化学对通过类似物将天然产品“命中分子”开发为合法的临床前铅化合物通过合成化学探针分子的结构 - 活性关系来鉴定结构活性关系作用研究机理等。有效的目标天然产物的总合成提供了可以从中解决这些关键研究领域的平台。拟议的研究很重要，因为化学合成将提供广泛的途径生物学上重要的二级代谢产物和类似物，以询问关键过程；在同时，基础合成设计和方法将导致田地的垂直进步有机化学。这些贡献是由化学驱动的，多方面的对具有免疫抑制，抗病毒，抗生素和神经活动；开发新的立体控制的多烯环化策略以访问多环芳烃天然产物；以及阐述新的激进式骑自行车策略以制造与生物活性天然产品相关的复杂体系结构。